PROJECT SUMMARY Progressive proteinuric kidney diseases are on the rise worldwide with more than 500 million people affected, and yet no effective therapies exist to halt their progression to kidney failure. High blood pressure and diabetes remain the biggest drivers of progressive kidney diseases worldwide. One big challenge is that the specific molecules and kidney cells involved in progression of kidney diseases remain poorly understood. Our recent work funded by this grant revealed two such molecules, Rac1 and TRPC5, as responsible for the injury and death of precious kidney cells called podocytes. Loss of podocytes resulted in proteinuria, the hallmark of a broken kidney filter barrier and ultimate kidney failure. Funded by this grant, we also discovered a TRPC5 blocker, called AC1903, which can prevent Rac1-TRPC5 from injuring podocytes. In two rat models of a kidney disease called FSGS (Focal and Segmental Glomerulosclerosis), we showed that AC1903 prevented kidney filter damage and protected podocytes, making this an excellent candidate for the development of a future therapy for patients. However, at this time, it is not clear if AC1903 or other TRPC channel blockers can be helpful in protecting the kidneys of patients with hypertension or diabetes-related kidney diseases. Therefore, the goal of this revised competitive renewal application is to build on our recent discoveries and perform careful and detailed studies in rat and mouse models of progressive kidney diseases to gain further insight into the role of TRPC ion channels and their blockers in the treatment of kidney diseases associated with hypertension and diabetes. This work will pave the way for new therapies for kidney disease patients, which are greatly needed.